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The archaic distinction between functioning and nonfunctioning neuroendocrine neoplasms is no longer clinically relevant

Langenbeck's Archives of Surgery volume 396, pages 1145–1156 (2011)Cite this article

Abstract

Background

Neuroendocrine neoplasms (NENs) are increasing in incidence and prevalence. This reflects greater clinical awareness, effective imaging, and increasing pathological diagnostic recognition. Although the identification and treatment of clinical neuroendocrine syndromes are established, there is confusion when a NEN has no discernible clinical symptoms.

Discussion

Nonfunctional tumors are usually diagnosed incidentally and at a later stage largely because either they do not secrete a bioactive product or do so, but in a form that is either inactive or in quantities that have no discernible effect. Nevertheless, the histopathology is indistinguishable from functional NENs, and tumors exhibit somatostatin receptor expression, and positive immunohistochemistry for neuroendocrine cell markers (CgA, NSE/synaptophysin). Similarly, their rates of growth and metastatic behavior are, like other NENs, predictably based on staging and grading (mitotic rate and Ki67 expression). Both types are diagnosed biochemically (CgA) and by imaging in an identical fashion with computed tomography, magnetic resonance imaging, somatostatin receptor scintigraphy, and endoscopic ultrasound. NENs, irrespective of function or bioactive secretory profile, respond with equal efficacy to the same regimen of surgery or antitumor drugs (e.g., somatostatin analogs with or without tyrosine kinase inhibitors/antiangiogenics or cytotoxics) depending on grade. Given the efficacy of somatostatin analogs in increasing progression free survival, nonfunctional NENs should be managed identically to symptomatic NENs. The consideration of NENs as functional or nonfunctional is an archaic clinical concept that should be discarded since the tumors are indistinguishable at a cellular, biological, and morphological level. All current evidences indicate that their diagnosis and treatment should follow the same common principles.

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References

  1. Modlin IM, Oberg K, Chung DC et al (2008) The current status of gastroenteropancreatic neuroendocrine tumors. Lancet Oncol 9:61–72

    PubMed  Article  CAS  Google Scholar 

  2. Yao JC, Hassan M, Phan A (2008) One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26(18):3063–3072

    PubMed  Article  Google Scholar 

  3. Modlin IM, Moss SF, Chung DC, Jensen RT, Snyderwine E (2008) Priorities for improving the management of gastroenteropancreatic neuroendocrine tumors. J Natl Cancer Inst 100(18):1282–1289

    PubMed  Article  Google Scholar 

  4. Schimmack S, Svejda B, Lawrence B, Kidd M, Modlin I (2011) The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors. Langenbeck's Archives 396(3):273–298

    Article  Google Scholar 

  5. Kent RB 3rd, van Heerden JA, Weiland LH (1981) Nonfunctioning islet cell tumors. Ann Surg 193(2):185–190

    PubMed  Article  Google Scholar 

  6. Nomura N, Fujii T, Kanazumi N et al (2009) Nonfunctioning neuroendocrine pancreatic tumors: our experience and management. J Hepatobiliary Pancreat Surg 16(5):639–647

    PubMed  Article  Google Scholar 

  7. Lawrence B, Gustafsson B, Chan A, Svejda B, Kidd M, Modlin I (2010) The epidemiology of gastroenteropancreatic tumors. Endocrinol Metab Clin North Am 40(1):1–18

    Article  Google Scholar 

  8. Franko J, Feng W, Yip L, Genovese E, Moser AJ (2010) Non-functional neuroendocrine carcinoma of the pancreas: incidence, tumor biology, and outcomes in 2,158 patients. J Gastrointest Surg 14(3):541–548

    PubMed  Article  Google Scholar 

  9. Chung TP, Hunt SR (2006) Carcinoid and neuroendocrine tumors of the colon and rectum. Clin Colon Rectal Surg 19(2):45–48

    PubMed  Article  Google Scholar 

  10. Onaitis MW, Kirshbom PM, Hayward TZ et al (2000) Gastrointestinal carcinoids: characterization by site of origin and hormone production. Ann Surg 232(4):549–556

    PubMed  Article  CAS  Google Scholar 

  11. Soreide O, Berstad T, Bakka A et al (1992) Surgical treatment as a principle in patients with advanced abdominal carcinoid tumors. Surgery 111(1):48–54

    PubMed  CAS  Google Scholar 

  12. Pape UF, Bohmig M, Berndt U, Tiling N, Wiedenmann B, Plockinger U (2004) Survival and clinical outcome of patients with neuroendocrine tumors of the gastroenteropancreatic tract in a german referral center. Ann NY Acad Sci 1014:222–233

    PubMed  Article  Google Scholar 

  13. Ekeblad S, Skogseid B, Dunder K, Oberg K, Eriksson B (2008) Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clin Cancer Res 14(23):7798–7803

    PubMed  Article  CAS  Google Scholar 

  14. Zerbi A, Falconi M, Rindi G et al (2010) Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases. Am J Gastroenterol 105(6):1421–1429

    PubMed  Article  Google Scholar 

  15. Broder LE, Carter SK (1973) Pancreatic islet cell carcinoma. I. Clinical features of 52 patients. Ann Intern Med 79(1):101–107

    PubMed  CAS  Google Scholar 

  16. Modlin IM, Gustafsson BI, Moss SF, Pavel M, Tsolakis AV, Kidd M (2010) Chromogranin A—biological function and clinical utility in neuro endocrine tumor disease. Ann Surg Oncol 17(9):2427–2443

    PubMed  Article  Google Scholar 

  17. Oberndorfer S. Karzinoide tumores des Dunndarms. Frankf Z Pathol. 1907:426–443

  18. DeLellis RA, Lloyd RV, Heitz PU, Eng C (eds) (2004) World Health Organization classification of tumours, pathology and genetics of tumours of endocrine organs. IARC, Lyon

    Google Scholar 

  19. Plockinger U, Rindi G, Arnold R et al (2004) Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology 80(6):394–424

    PubMed  Article  CAS  Google Scholar 

  20. Bosman F, Carneiro F, Hruban R, Theise N (2010) WHO classification of tumours of the digestive system. WHO/IARC, Lyon

    Google Scholar 

  21. Klimstra DS, Modlin IM, Adsay NV et al (2010) Pathologic reporting of neuroendocrine tumors: Application of the Delphic consensus process to the development of a minimum pathologic data set. Am J Surg Pathol 34(3):300–313

    PubMed  Article  Google Scholar 

  22. Metz DC (1999) Diagnosis of non-Zollinger-Ellison syndrome, non-carcinoid syndrome, enteropancreatic neuroendocrine tumours. Ital J Gastroenterol Hepatol 31(Suppl 2):S153–S159

    PubMed  Google Scholar 

  23. Oberg K, Skogseid B (1998) The ultimate biochemical diagnosis of endocrine pancreatic tumours in MEN-1. J Intern Med 243(6):471–476

    PubMed  Article  CAS  Google Scholar 

  24. Stivanello M, Berruti A, Torta M (2001) Circulating chromogranin A in the assessment of patients with neuroendocrine tumours. A single institution experience. Ann Oncol 12(Suppl 2):S73–S77

    PubMed  Article  Google Scholar 

  25. Oberg K, Eriksson B (2005) Endocrine tumours of the pancreas. Best Pract Res Clin Gastroenterol 19(5):753–781

    PubMed  Article  Google Scholar 

  26. Jensen RT, Niederle B, Mitry E et al (2006) Gastrinoma (duodenal and pancreatic). Neuroendocrinology 84(3):173–182

    PubMed  Article  CAS  Google Scholar 

  27. Zhao J, Moch H, Scheidweiler AF et al (2001) Genomic imbalances in the progression of endocrine pancreatic tumors. Genes Chromosom Cancer 32(4):364–372

    PubMed  Article  CAS  Google Scholar 

  28. Forget MA, Turcotte S, Beauseigle D (2007) The Wnt pathway regulator DKK1 is preferentially expressed in hormone-resistant breast tumours and in some common cancer types. Br J Cancer 96(4):646–653

    PubMed  Article  CAS  Google Scholar 

  29. Gonzalez-Sancho JM, Aguilera O, Garcia JM et al (2005) The Wnt antagonist DICKKOPF-1 gene is a downstream target of beta-catenin/TCF and is downregulated in human colon cancer. Oncogene 24(6):1098–1103

    PubMed  Article  CAS  Google Scholar 

  30. Johansson TA, Westin G, Skogseid B (2009) Identification of Achaete-scute complex-like 1 (ASCL1) target genes and evaluation of DKK1 and TPH1 expression in pancreatic endocrine tumours. BMC Cancer 9:321

    PubMed  Article  Google Scholar 

  31. Jiao Y, Shi C, Edil BH et al (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331(6021):1199–203

    PubMed  Article  CAS  Google Scholar 

  32. Floridia G, Grilli G, Salvatore M et al (2005) Chromosomal alterations detected by comparative genomic hybridization in nonfunctioning endocrine pancreatic tumors. Cancer Genet Cytogenet 156(1):23–30

    PubMed  Article  CAS  Google Scholar 

  33. Rigaud G, Missiaglia E, Moore PS et al (2001) High resolution allelotype of nonfunctional pancreatic endocrine tumors: identification of two molecular subgroups with clinical implications. Cancer Res 61(1):285–292

    PubMed  CAS  Google Scholar 

  34. Woodard PK, Feldman JM, Paine SS, Baker ME (1995) Midgut carcinoid tumors: CT findings and biochemical profiles. J Comput Assist Tomogr 19(3):400–405

    PubMed  Article  CAS  Google Scholar 

  35. Kaltsas GA, Besser GM, Grossman AB (2004) The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev 25(3):458–511

    PubMed  Article  CAS  Google Scholar 

  36. Garbrecht N, Anlauf M, Schmitt A et al (2008) Somatostatin-producing neuroendocrine tumors of the duodenum and pancreas: incidence, types, biological behavior, association with inherited syndromes, and functional activity. Endocr Relat Cancer 15(1):229–241

    PubMed  Article  Google Scholar 

  37. Rinke A, Muller HH, Schade-Brittinger C et al (2009) Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 27:4656–4663

    PubMed  Article  CAS  Google Scholar 

  38. Ganti AK, West WW, Lackner RP, Kessinger A (2010) Current concepts in the diagnosis and management of small-cell lung cancer. Oncology (Williston Park) 24(11):1034–1039

    Google Scholar 

  39. Stridsberg M, Oberg K, Li Q et al (1995) Measurement of chromogranin A, chromogranin B (secretogranin I), chromogranin C (secretogranin II) and pancreastatin in plasma and urine from patients with carcinoid tumours and endocrine pancreatic tumours. J Endocrinol 144:49–59

    PubMed  Article  CAS  Google Scholar 

  40. Rorstad O (2005) Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract. J Surg Oncol 89:151–160

    PubMed  Article  Google Scholar 

  41. Stridsberg M, Eriksson B, Oberg K, Janson ET (2003) A comparison between three commercial kits for chromogranin A measurements. J Endocrinol 177(2):337–341

    PubMed  Article  CAS  Google Scholar 

  42. Panzuto F, Severi C, Cannizzaro R et al (2004) Utility of combined use of plasma levels of chromogranin A and pancreatic polypeptide in the diagnosis of gastrointestinal and pancreatic endocrine tumors. J Endocrinol Investig 27(1):6–11

    CAS  Google Scholar 

  43. Nikou GC, Marinou K, Thomakos P et al (2008) Chromogranin a levels in diagnosis, treatment and follow-up of 42 patients with non-functioning pancreatic endocrine tumours. Pancreatology 8(4–5):510–519

    PubMed  Article  CAS  Google Scholar 

  44. Wu TJ, Lin CL, Taylor RL, Kvols LK, Kao PC (1997) Increased parathyroid hormone-related peptide in patients with hypercalcemia associated with islet cell carcinoma. Mayo Clin Proc 72(12):1111–1115

    PubMed  Article  CAS  Google Scholar 

  45. Corbetta S, Peracchi M, Cappiello V et al (2003) Circulating ghrelin levels in patients with pancreatic and gastrointestinal neuroendocrine tumors: identification of one pancreatic ghrelinoma. J Clin Endocrinol Metab 88(7):3117–3120

    PubMed  Article  CAS  Google Scholar 

  46. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD (2005) Current status of gastrointestinal carcinoids. Gastroenterology 128(6):1717–1751

    PubMed  Article  Google Scholar 

  47. Murugesan SV, Varro A, Pritchard DM (2009) Review article: strategies to determine whether hypergastrinaemia is due to Zollinger-Ellison syndrome rather than a more common benign cause. Aliment Pharmacol Ther 29(10):1055–1068

    PubMed  Article  CAS  Google Scholar 

  48. Marko J, Lamba R, Miller F, Buchman A, Spies S, Nikolaidis P (2008) OctreoScan positive Crohn's disease mimicking an ileal carcinoid tumor. J Clin Gastroenterol 42(1):66–68

    PubMed  Article  Google Scholar 

  49. Hofmann M, Maecke H, Borner R et al (2001) Biokinetics and imaging with the somatostatin receptor PET radioligand (68)Ga-DOTATOC: preliminary data. Eur J Nucl Med 28(12):1751–1757

    PubMed  Article  CAS  Google Scholar 

  50. Papotti M, Bongiovanni M, Volante M et al (2002) Expression of somatostatin receptor types 1–5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Arch 440(5):461–475

    PubMed  Article  CAS  Google Scholar 

  51. Missiaglia E, Dalai I, Barbi S et al (2010) Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol 28(2):245–255

    PubMed  Article  CAS  Google Scholar 

  52. Kimura N, Pilichowska M, Date F, Kimura I, Schindler M (1999) Immunohistochemical expression of somatostatin type 2A receptor in neuroendocrine tumors. Clin Cancer Res 5(11):3483–3487

    PubMed  CAS  Google Scholar 

  53. Kulaksiz H, Eissele R, Rossler D et al (2002) Identification of somatostatin receptor subtypes 1, 2A, 3, and 5 in neuroendocrine tumours with subtype specific antibodies. Gut 50(1):52–60

    PubMed  Article  CAS  Google Scholar 

  54. Fjallskog ML, Ludvigsen E, Stridsberg M, Oberg K, Eriksson B, Janson ET (2003) Expression of somatostatin receptor subtypes 1 to 5 in tumor tissue and intratumoral vessels in malignant endocrine pancreatic tumors. Med Oncol 20(1):59–67

    PubMed  Article  Google Scholar 

  55. Corleto VD, Falconi M, Panzuto F et al (2009) Somatostatin receptor subtypes 2 and 5 are associated with better survival in well-differentiated endocrine carcinomas. Neuroendocrinology 89(2):223–230

    PubMed  Article  CAS  Google Scholar 

  56. Pais SA, Al-Haddad M, Mehdi M et al (2010) EUS for pancreatic neuroendocrine tumors: a single-center, 11-year experience. Gastrointest Endosc 71(7):1185–1193

    PubMed  Article  Google Scholar 

  57. Norton JA, Fraker DL, Alexander HR et al (2006) Surgery increases survival in patients with gastrinoma. Ann Surg 244(3):410–419

    PubMed  Google Scholar 

  58. Chamberlain RS, Canes D, Brown KT et al (2000) Hepatic neuroendocrine metastases: does intervention alter outcomes? J Am Coll Surg 190(4):432–445

    PubMed  Article  CAS  Google Scholar 

  59. O'Toole D, Ruszniewski P (2005) Chemoembolization and other ablative therapies for liver metastases of gastrointestinal endocrine tumours. Best Pract Res Clin Gastroenterol 19(4):585–594

    PubMed  Article  Google Scholar 

  60. O'Toole D, Maire F, Ruszniewski P (2003) Ablative therapies for liver metastases of digestive endocrine tumours. Endocr Relat Cancer 10(4):463–468

    PubMed  Article  Google Scholar 

  61. van Vilsteren FG, Baskin-Bey ES, Nagorney DM et al (2006) Liver transplantation for gastroenteropancreatic neuroendocrine cancers: Defining selection criteria to improve survival. Liver Transpl 12(3):448–456

    PubMed  Article  Google Scholar 

  62. Modlin I, Pavel M, Kidd M, Gustafsson B (2010) Somatostatin analogues: an appraisal of their utility and efficacy. Aliment Pharmacol Ther 31(2):169–188

    PubMed  CAS  Google Scholar 

  63. Kulke MH, Hornick JL, Frauenhoffer C et al (2009) O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res 15(1):338–345

    PubMed  Article  CAS  Google Scholar 

  64. Janson ET, Sorbye H, Welin S et al (2010) Nordic Guidelines 2010 for diagnosis and treatment of gastroenteropancreatic neuroendocrine tumours. Acta Oncol 49(6):740–756

    PubMed  Article  CAS  Google Scholar 

  65. Kulke MH (2007) Clinical presentation and management of carcinoid tumors. Hematol Oncol Clin North Am 21(3):433–455, vii-viii

    PubMed  Article  Google Scholar 

  66. Moertel CG, Kvols LK, O'Connell MJ, Rubin J (1991) Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 68(2):227–232

    PubMed  Article  CAS  Google Scholar 

  67. Modlin IM, Kidd M, Drozdov I, Siddique ZL, Gustafsson BI (2008) Pharmacotherapy of neuroendocrine cancers. Expert Opin Pharmacother 9(15):2617–2626

    PubMed  Article  CAS  Google Scholar 

  68. Pavel M, Hainsworth JD, Baudin E, et al. (2010) A randomized, double-blind, placebo-controlled, multicenter phase III trial of everolimus + octreotide lar vs placebo + octreotide LAR in patients with advanced neuroendocrine tumors (NET) (RADIANT-2). Ann Oncol 21(Suppl 8):Abst LBA8

  69. Yao JC, Shah MH, Ito T, et al. (2010) A randomized, double-blind, placebo-controlled, multicenter phase iii trial of everolimus in patients with advanced pancreatic neuroendocrine tumors (PNET) (RADIANT-3). Ann Oncol 21(Suppl 8):Abst LBA9

  70. Kulke M, Blaszkowsky L, Zhu A, Flortio S, Regan E (2010 ) Phase I/II study of everolimus (RAD001) in combination with Temozolamide (TMZ) in patients (pts) with advanced pancreatic neuroendocrine tumors (NET). Proc Am Soc Clin Oncol Gast Int:Abstr 223

  71. Kulke MH, Stuart K, Enzinger PC et al (2006) Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24(3):401–406

    PubMed  Article  CAS  Google Scholar 

  72. van Essen M, Krenning EP, Kam BL, de Jong M, Valkema R, Kwekkeboom DJ (2009) Peptide-receptor radionuclide therapy for endocrine tumors. Nat Rev Endocrinol 5(7):382–393

    PubMed  Article  Google Scholar 

  73. Scarpa A, Mantovani W, Capelli P et al (2010) Pancreatic endocrine tumors: improved TNM staging and histopathological grading permit a clinically efficient prognostic stratification of patients. Mod Pathol 23(6):824–833

    PubMed  Article  CAS  Google Scholar 

  74. Pape UF, Jann H, Muller-Nordhorn J et al (2008) Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer 113(2):256–265

    PubMed  Article  Google Scholar 

  75. Pomianowska E, Gladhaug IP, Grzyb K et al (2010) Survival following resection of pancreatic endocrine tumors: importance of R-status and the WHO and TNM classification systems. Scand J Gastroenterol 45(7–8):971–979

    PubMed  Article  Google Scholar 

  76. Panzuto F, Nasoni S, Falconi M et al (2005) Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer 12(4):1083–1092

    PubMed  Article  Google Scholar 

  77. Yao JC, Shah MH, Ito T et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364(6):514–523

    PubMed  Article  CAS  Google Scholar 

  78. Raymond E, Dahan L, Raoul JL et al (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364(6):501–513

    PubMed  Article  CAS  Google Scholar 

  79. Tanimoto A, Matsuki Y, Tomita T, Sasaguri T, Shimajiri S, Sasaguri Y (2004) Histidine decarboxylase expression in pancreatic endocrine cells and related tumors. Pathol Int 54(6):408–412

    PubMed  Article  CAS  Google Scholar 

  80. Bordi C, Pilato FP, D'Adda T (1988) Comparative study of seven neuroendocrine markers in pancreatic endocrine tumours. Virchows Arch A Pathol Anat Histopathol 413(5):387–398

    PubMed  Article  CAS  Google Scholar 

  81. Lloyd RV, Mervak T, Schmidt K, Warner TF, Wilson BS (1984) Immunohistochemical detection of chromogranin and neuron-specific enolase in pancreatic endocrine neoplasms. Am J Surg Pathol 8(8):607–614

    PubMed  Article  CAS  Google Scholar 

  82. Chejfec G, Falkmer S, Grimelius L et al (1987) Synaptophysin. A new marker for pancreatic neuroendocrine tumors. Am J Surg Pathol Apr 11(4):241–247

    Article  CAS  Google Scholar 

  83. Simpson S, Vinik AI, Marangos PJ, Lloyd RV (1984) Immunohistochemical localization of neuron-specific enolase in gastroenteropancreatic neuroendocrine tumors. Correlation with tissue and serum levels of neuron-specific enolase. Cancer 54(7):1364–1369

    PubMed  Article  CAS  Google Scholar 

  84. Tomita T, Kimmel JR, Friesen SR, Doull V, Pollock HG (1985) Pancreatic polypeptide in islet cell tumors. Morphologic and functional correlations. Cancer 56(7):1649–1657

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

MK was supported in part by NIH: DK080871. BL was supported in part by a grant from the Genesis Oncology Trust, Auckland, New Zealand.

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Affiliations

  1. Gastrointestinal Pathobiology Group, Yale University School of Medicine, 310 Cedar Street, New Haven, CT, BML212, USA

    Irvin M. Modlin, Ben Lawrence, Simon Schimmack & Mark Kidd

  2. Liver Research Center, Brown University, Providence, RI, 02903, USA

    Steven F. Moss

  3. Department of Gastroenterology, St Olavs Hospital, Norwegian University of Science and Technology, Prinsesse Kristinas gate 1, 7006, Trondheim, Norway

    Bjorn I. Gustafsson

  4. Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Prinsesse Kristinas gate 1, 7006, Trondheim, Norway

    Bjorn I. Gustafsson

  5. Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany

    Simon Schimmack

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  1. Irvin M. Modlin
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Modlin, I.M., Moss, S.F., Gustafsson, B.I. et al. The archaic distinction between functioning and nonfunctioning neuroendocrine neoplasms is no longer clinically relevant. Langenbecks Arch Surg 396, 1145–1156 (2011). https://doi.org/10.1007/s00423-011-0794-7

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Keywords

  • Carcinoid
  • Functional
  • Epidemiology
  • Incidence
  • Nonfunctional
  • Pancreatic neuroendocrine tumor
  • SEER
  • Survival